Five missense variants in the amino-terminal domain of the glucocorticoid receptor: No association with puerperal psychosis or schizophrenia

Steroid hormone administration causes behavior changes in many and psychosi s in a few. The clinical features suggest that genetic variants of the gluc ocorticoid receptor or cofactors could produce susceptible subpopulations w ho react adversely to hormonal cascades. To investigate this possibility, c oding and splice site sequences of the glucocorticoid receptor were scanned for single nucleotide polymorphisms in genomic DNA samples from 100 schizo phrenics (86 Caucasians and 14 African-Americans) and 40 Caucasians with pu erperal psychosis. Five amino acid substitutions were found in the amino-te rminal domain at frequencies of 0.6 to 3.8% in Caucasians: R23K, F29L, L112 F, D233N, and N363S, In addition, four silent nucleotide changes were found : E22E, K293K, D677D, and N766N; a transversion in intron 4 occurred beyond the splice junction. None of these variants can be linked to these disorde rs at present. However, the N363S variant contributes a new potential phosp horylation site and has been associated with increased body mass and reduce d bone mineral density [Huizenga et al,, 1998: J Clin Endocrinol Metab 83:1 44-151], so it is possible that the other missense variants confer traits t hat currently are unrecognized, Comparisons to natural glucocorticoid recep tor mutants in the familial glucocorticoid resistance syndrome and steroid resistant leukemias suggest that amino acid substitutions at highly conserv ed residues may cause severe functional defects and serious illness, while changes at less conserved sites produce lesser alterations and milder disea se. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:412-417, 2000. (C) 2000 Wiley-Liss, Inc.